Progesterone is essential for the normal morphological development of the luteal phase endometrium, for implantation of a blastocyst and for maintenance of pregnancy. Surprisingly, given its critical role in reproduction, little is known about the mediator(s) of progesterone action. We are using a recently described progestin-dependent glycoprotein, placental protein 14(PP14) and the antiprogestin RU 486 to probe progesterone action. We are investigating the relationship between endogenous progesterone production, serum PP14 concentrations and endometrial maturation in women with normal cycles. Up to 28% of normally cycling women has a delay in endometrial maturation of a biopsy obtained 7-9 days after the LH surge. Contrary to previous studies from other groups, the integrated and peak levels of PP14 and progesterone did not correlate with the degree of endometrial maturation. Only two of 14 women having abnormal endometrial development had progesterone values below the range seen in women with normal endometrial development. These studies suggest that measurement of serum PP14 and progesterone concentrations may not be useful predictors of fecundity in normally cycling women. Further studies in fertile women and those with multiple miscarriages may give better insight into the cause of these disorders, however, since it is possible that the progesterone-mediated endometrial effects may be abnormal in these subgroups. We have used the antiprogestin RU 486 to probe the utility of antiprogestin compounds as contraceptive agents. Studies in non-pregnant women show that small daily doses of RU 486 delay the normal maturation of the endometrium without changing the hormonal patterns or timing of the menstrual cycle. Serum PP14 concentrations were decreased significantly in the women receiving RU 486, showing that progesterone (and not some other product of the corpus luteum) is critical for normal endometrial function. No adverse effects were seen. These data suggest that RU 486 has potential as a contraceptive agent.